ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2012
Repeated stress dysregulates κ-opioid receptor signaling in the dorsal raphe through a p38α MAPK-dependent mechanism.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 63 citations in OpenAlex.
- Effects of SSRIs on the spatial transcriptome of dorsal raphe serotonin neurons.Molecular psychiatry · 2026Article
- G Protein Inactivation as a Mechanism for Addiction Treatment.Biological psychiatry · 2026Article
- Animal Models of Prenatal Opioid Exposure: Insights into Impaired Neurodevelopment.Advances in experimental medicine and biology · 2026Review
- κ-Opioid Receptor Agonists as Robust Pain-Modulating Agents: Mechanisms and Therapeutic Potential in Pain Modulation.Journal of clinical medicine · 2025Review
- A switch in kappa opioid receptor signaling from inhibitory to excitatory induced by stress in a subset of cortically-projecting dopamine neurons.bioRxiv : the preprint server for biology · 2025Article
- Mitogen-activated protein kinase dependent presynaptic potentiation in the lateral habenula mediates depressive-like behaviors in rats.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2025Article
- Heightened lateral habenula activity during stress produces brainwide and behavioral substrates of susceptibility.Neuron · 2024Article
- Interaction between corticotropin-releasing factor, orexin, and dynorphin in the infralimbic cortex may mediate exacerbated alcohol-seeking behavior.Neurobiology of stress · 2024Article
- Co-targeting the kappa opioid receptor and dopamine transporter reduces motivation to self-administer cocaine and partially reverses dopamine system dysregulation.Scientific reports · 2024Article
- Endogenous opioid system modulates conditioned cocaine reward in a sex-dependent manner.Addiction biology · 2023Article
- Key differences in regulation of opioid receptors localized to presynaptic terminals compared to somas: Relevance for novel therapeutics.Neuropharmacology · 2023Review
- Kappa Opioid Receptors Reduce Serotonin Uptake and Escitalopram Efficacy in the Mouse Substantia Nigra Pars Reticulata.International journal of molecular sciences · 2023Article
- Modulation of 5-HT release by dynorphin mediates social deficits during opioid withdrawal.Neuron · 2022Article
- Neuronal G protein-gated KAmerican journal of physiology. Cell physiology · 2022Review
- Article
- Stress decreases serotonin tone in the nucleus accumbens in male mice to promote aversion and potentiate cocaine preference via decreased stimulation of 5-HTNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2022Article
- Release of endogenous dynorphin opioids in the prefrontal cortex disrupts cognition.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2021Article
- A midbrain dynorphin circuit promotes threat generalization.Current biology : CB · 2021Article
- The Role of the Kappa Opioid System in Comorbid Pain and Psychiatric Disorders: Function and Implications.Frontiers in neuroscience · 2021Review
- Functions of p38 MAP Kinases in the Central Nervous System.Frontiers in molecular neuroscience · 2020Review
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 3 countries.
Funding
Abstract
Repeated stress releases dynorphins and causes subsequent activation of κ-opioid receptors (KORs) in limbic brain regions. The serotonergic dorsal raphe nucleus (DRN) has previously been found to be an important site of action for the dysphoric effects of dynorphin-κ-opioid receptor system activation during stress-evoked behaviors, and KOR-induced activation of p38α mitogen-activated protein kinase (MAPK) in serotonergic neurons was found to be a critical mediator of the aversive properties of stress. Yet, how dynorphins and KORs functionally regulate the excitability of serotonergic DRN neurons both in adaptive and pathological stress states is poorly understood. Here we report that acute KOR activation by the selective agonist U69,593 [(+)-(5α,7α,8β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamide] inhibits serotonergic neuronal excitability within the DRN through both presynaptic inhibition of excitatory synaptic transmission and postsynaptic activation of G-protein-gated inwardly rectifying potassium channels (GIRKs) electrophysiologically recorded in brain slices. C57BL/6 mice subjected to repeated swim, stress sessions had significantly reduced KOR-mediated GIRK currents recorded in serotonergic neurons in DRN postsynaptically, without significantly affecting presynaptic KOR-mediated regulation of excitatory transmission. This effect was blocked by genetic excision of p38α MAPK selectively from serotonergic neurons. An increase in phospho-immunoreactivity suggests that this functional dysregulation may be a consequence of tyrosine phosphorylation of GIRK (K(IR)3.1) channels. These data elucidate a mechanism for stress-induced dysregulation of the excitability of neurons in the DRN and identify a functional target of stress-induced p38α MAPK activation that may underlie some of the negative effects of pathological stress exposure.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.